This invention relates to a method for the synthesis of mannojirimycin derivatives and, more particularly, to the synthesis of .alpha.-homomannojirimycin and 6-epi-homomannojirimycin from the azidolactone, 2-azido-2-deoxy-3,4:6,7-di-O-isopropylidene-D-glycero-D-talo-heptono-1,5-l actone.
Iminoheptitols, such as .alpha.-homonojirimycin (1) may constitute a general class of glycosidase inhibitors in which it is possible to use the anomeric substituent to obtain additional potency and/or specificity in comparison to the corresponding azohexoses that lack such a substituent. For example, the .beta.-glucopyranosyl derivative (2) [Anzeveno et al., J. Org. Chem., 54, 2539 (1989); Liu, J. Org. Chem., 52, 4717 (1987)]of .alpha.-homonojirimycin (1), the first example of a naturally occurring azoheptose [Kite, et al., Tetrahedron Lett., 29, 6483 (1988)], is a powerful .alpha.-glucosidase inhibitor and is a drug candidate for antidiabetic therapy [Rhinehart et al., J. Pharmacol. Exp. Therap., 241, 915 (1987)]. Also, homofuconojirimycin (3) [Fleet et al., Tetrahedron Lett., 30, 4439 (1989)]is as powerful an inhibitor of human liver .alpha.-fucosidase as is deoxyfuconojirimycin (4) [Winchester et al., Biochem. J., 259, in press (1989).
Deoxymannojirimycin (DMJ) (5) is a major biochemical tool for the investigation and inhibition of mannosidases of glycoprotein processing [Elbein, Ann. Rev. Biochem., 56, 497 (1987)], although it is a relatively weak inhibitor of .alpha.-mannosidases in general. It has been suggested that DMJ may attenuate the infectivity of HIV-1 [Montefiori et al., Proc. Natl. Acad. Sci. USA 85, 9248 (1988)]due to its inhibition of processing mannosidases, and molecular graphics studies have been reported in an attempt to design mannosidase inhibitors as potential anti-HIV agents [Winkler and Holan, J. Med. Chem. 32, 2084 (1989)]. In fact, DMJ is a better inhibitor of .alpha.-fucosidases than of .alpha.-mannosidases [Evans et al. Phytochemistry, 24, 1953 (1985)]. This is presumably due to the correspondence of the stereochemistry of the hydroxyl functions at C-2, C-3 and C-4 of DMJ with those in both mannose and fucose and the less stringent structural requirements for the inhibition of .alpha.-fucosidase than of .alpha.-mannosidase. .alpha.-Homomannojirimycin (HMJ) (6) may be a more specific inhibitor of mannosidase than is DMJ (5) because of the additional interaction of the anomeric substituent with the active site of .alpha.-mannosidases. Furthermore, HMJ (6) should be a relatively weak inhibitor of .alpha.-fucosidases since the configurations at C-2 and C-6 are incorrect in relation to .alpha.-fuco configuration; the presence of the polar hydroxymethyl--rather than a methyl--substituent at C-6 should also decrease fucosidase inhibition. Additionally, HMJ should allow the preparation of a number of .alpha.-mannosyl derivatives (7) which might allow differential inhibition of the different mannosidases of glycoprotein processing, depending on the nature of the link to the mannose residue. ##STR1##
Homomannojirimycin contains five adjacent chiral centers and seven adjacent carbon atoms, bearing functional groups. Previous syntheses of this class of compounds [Anzeveno et al., supra; Liu, supra; and Fleet et al., Tetrahedron Lett. 30, 4439 (1989)], begin with hexose derivatives and add the additional carbon atom relatively late in the synthesis.